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CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms.

Nature genetics | May 13, 2012

Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh(tn222)) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.

Pubmed ID: 22581229 RIS Download

Mesh terms: Animals | Cilia | Dyneins | Female | Humans | Kartagener Syndrome | Male | Mutation | Pedigree | Zebrafish

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM051293
  • Agency: Medical Research Council, Id: F32DK083868
  • Agency: NIDDK NIH HHS, Id: R01 GM056211
  • Agency: NIGMS NIH HHS, Id: R01 DK053093
  • Agency: NIDDK NIH HHS, Id: DK053093
  • Agency: NIDDK NIH HHS, Id: F32 DK083868
  • Agency: NIDDK NIH HHS, Id: R01 DE016779
  • Agency: NIDCR NIH HHS, Id: R01 GM051293
  • Agency: NIGMS NIH HHS, Id:
  • Agency: Wellcome Trust, Id:

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1000 Genomes: A Deep Catalog of Human Genetic Variation

International collaboration producing an extensive public catalog of human genetic variation, including SNPs and structural variants, and their haplotype contexts, in an effort to provide a foundation for investigating the relationship between genotype and phenotype. The genomes of about 2500 unidentified people from about 25 populations around the world were sequenced using next-generation sequencing technologies. Redundant sequencing on various platforms and by different groups of scientists of the same samples can be compared. The results of the study are freely and publicly accessible to researchers worldwide. The consortium identified the following populations whose DNA will be sequenced: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Chinese in Beijing; Utah residents with ancestry from northern and western Europe; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Toscani in Italy; Gujarati Indians in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States. The goal Project is to find most genetic variants that have frequencies of at least 1% in the populations studied. Sequencing is still too expensive to deeply sequence the many samples being studied for this project. However, any particular region of the genome generally contains a limited number of haplotypes. Data can be combined across many samples to allow efficient detection of most of the variants in a region. The Project currently plans to sequence each sample to about 4X coverage; at this depth sequencing cannot provide the complete genotype of each sample, but should allow the detection of most variants with frequencies as low as 1%. Combining the data from 2500 samples should allow highly accurate estimation (imputation) of the variants and genotypes for each sample that were not seen directly by the light sequencing. All samples from the 1000 genomes are available as lymphoblastoid cell lines (LCLs) and LCL derived DNA from the Coriell Cell Repository as part of the NHGRI Catalog. The sequence and alignment data generated by the 1000genomes project is made available as quickly as possible via their mirrored ftp sites. ftp://ftp.1000genomes.ebi.ac.uk ftp://ftp-trace.ncbi.nlm.nih.gov/1000genomes

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PolyPhen-2

A tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations.

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